The Candidate: Dr. Lisa Berman-Booty is a licensed veterinarian currently enrolled in the combined anatomic pathology residency and graduate research-training program in the Department of Veterinary Biosciences at The Ohio State University. The funding provided by the K01 SERCA would support Dr. Berman-Booty for the next five years of her career, which will include her final two years of graduate school (culminating with the completion of her Ph.D.) and her first three-years as an independent principal investigator. The Environment: Dr. Berman-Booty's training will be coordinated through the Department of Veterinary Biosciences, a multidisciplinary research environment that combines multiple research disciplines into a cohesive academic unit. The resources, guidance, and collaborations provided by the faculty members in the department will enable Dr. Berman-Booty to develop into a successful independent scientist. Dr. Berman- Booty's primary mentor, Dr. Ching-Shih Chen, is a Professor of Medicinal Chemistry at The Ohio State University College of Pharmacy. Dr. Chen is an expert in the field of medicinal chemistry and the development of novel chemotherapeutics. He has mentored many graduate students and postdoctoral fellows. Dr. Thomas Rosol and Dr. Steven Clinton, members of Dr. Berman-Booty's mentorship committee, have expertise in the study of urogenital cancer, prostate pathology, chemoprevention, and mouse models of human cancer. The Training and Career Development Plans: Training and career development during this award period will include the mastery of new techniques in molecular biology, study of the newest developments in the field of cancer research, and further refinement of grantsmanship and manuscript writing skills. The primary mentor and the mentorship committee will closely supervise the training. The five-year training plan consists of two phases. K award funding during phase I (years 1 and 2) will allow Dr. Berman-Booty to devote approximately 90% of her time to research and include the completion of her Ph.D. K award funding during phase II (years 3, 4, and 5) will allow Dr. Berman-Booty to transition to a position as a junior faculty member. Career Goals: Dr. Berman-Booty's immediate career goals include completing the research for her dissertation and becoming an independent research scientist and junior faculty member at the Ohio State University. Her long-term career goals are to obtain a tenure track position at an academic institution, develop additional animal models of human cancer, and continue her research into cancer prevention and treatment. The Proposal: A hallmark of cancer cells is a shift in cellular energy metabolism to aerobic glycolysis (the Warburg effect). This is associated with increased glycolytic flux and energy metabolism. While this metabolic shift provides growth advantages to cancer cells, it also presents opportunities to exploit the peculiarities of tumor cell metabolism for therapeutic and/or chemopreventive purposes. Dietary energy restriction has been effective in suppressing carcinogenesis in various animal models. Additionally, recent research has demonstrated the in vitro and in vivo antitumor efficacies of the energy restriction mimetic agents (ERMAs) 2- deoxyglucose (2-DG) and resveratrol. However, the utilization of energy restriction as a means of human cancer prevention and treatment is untenable, and the anti-tumor potencies of 2-DG and resveratrol are relatively low. We have recently developed two novel ERMAs, derived from the thiazolidinedione ciglitazone, that exhibit higher in vitro potency than 2-DG and resveratrol. The focus of this grant application is to evaluate the effects of these ERMAs (CG12 and CG5) in preclinical models of prostate cancer. The central hypothesis to be tested is that the unique abilities of CG12 and CG5 to target energy metabolism have translational potential in prostate cancer prevention. To test this hypothesis, we will utilize human prostate cancer cell lines, xenograft mouse models, and transgenic mice that autochthonously develop prostate cancer. PUBLIC HEALTH RELEVANCE: Prostate cancer is the second leading cause of cancer related death in American men. Current therapies for disseminated prostate cancer include hormonal ablation either via surgical or medical castration. Because of the deleterious side effects associated with the aforementioned treatments and the eventual recurrence of castration-resistant disease, novel therapies and preventive strategies are needed. The overall goal of this research is to investigate the mechanism of action of the novel ERMAs CG12 and CG5 and determine their in vivo tumor suppressive and chemopreventive activities. We hope that our results will show that one or both agents are suitable for future human clinical trials.